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Cognitive dysfunction in Parkinson's disease related to the R1441G mutation in LRRK2
Parkinsonism and Related Disorders 20 (2014) 1097e1100
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Cognitive dysfunction in Parkinson's disease related to the R1441G mutation in LRRK2 A. Estanga a, d, *, M.C. Rodriguez-Oroz a, b, c, J. Ruiz-Martinez a, b, M. Barandiaran a, b, A. Gorostidi a, A. Bergareche a, b, E. Mondragon a, b, A. Lopez de Munain a, b, d, J.F. Marti-Masso a, b, d a
Neuroscience Unit, Biodonostia Research Institute, San Sebastian, Spain Department of Neurology, University Hospital Donostia, San Sebastian, Spain Ikerbasque, Basque Foundation for Science, Bilbao, Spain d Department of Neuroscience, University of the Basque Country UPV/EHU, Spain b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 December 2013 Received in revised form 23 June 2014 Accepted 9 July 2014
Objective: The neuropsychological characteristics of patients with Parkinson's Disease (PD) associated with R1441G mutation in the LRRK2 gene (R1441G-PD) are not well known. The aim of this study was to examine the cognitive status and mood of R1441G-PD patients. Methods: Thirty patients with R1441G-PD were compared with thirty idiopathic PD (i-PD) patients who were matched by age, sex, education, disease onset age and duration, using a comprehensive battery of neuropsychological test, and considering the Movement Disorder Society (MDS) criteria for the diagnosis of Mild Cognitive Impairment (PD-MCI) and dementia (PD-Dementia). Results: The mean scores in the depression and anxiety scales were similar in the two groups. Depressive symptoms were detected in 31.8% of R1441G-PD and 25% of i-PD patients and anxiety symptoms were evident in 4.5% and 15%, respectively, but the differences were not significant. The only neuropsychological test on which there was a significantly worse performance in the R1441G-PD group was the Boston naming test but the difference became not significant when Bonferroni's correction was applied. The prevalence of PD-MCI was 30% in both R1441G-PD and i-PD, with no differences in the number and type of domains altered given that executive function, memory and attention were mainly affected. PDDementia was diagnosed in 13.3% (n ¼ 4) of R1441G-PD and 26.7% (n ¼ 8) of i-PD patients (difference was not significant). Conclusion: In conclusion, significant differences were not detected between R1441G-PD and i-PD in cognitive, depression and anxiety scales, or PD-MCI and PD-Dementia prevalence, and the cognitive profile was identical in the two groups. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Cognitive impairment Mood Parkinson's disease R1441G mutation LRRK2
1. Background LRRK2 mutations are the most common known genetic cause of autosomal dominant PD. The LRRK2-R1441G mutation has been found to be responsible of 46% of familial PD and 2.5% of sporadic PD in patients of basque origin in Gipuzkoa (Spain) [1]. The R1441G mutation is also identified at lower frequencies in patients from
* Corresponding author. Neurology Department, University Hospital Donostia, Paseo Dr. Beguiristain 107-116, 20014, San Sebastian, Spain. Tel.: þ34 943007145. E-mail addresses: [email protected], ainaraestanga@gmail. com (A. Estanga). http://dx.doi.org/10.1016/j.parkreldis.2014.07.005 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
nearby provinces (2.2% in Asturias [2], 1% in Cantabria [3], 0.7% in Catalonia [4]) but it is very rare outside Northern Spain. The clinical features of PD patients with this mutation are similar to those with sporadic PD, although a more “benign” progression of the disease evolving less often into dementia has been reported [2]. Nevertheless, the neuropsychological features of these patients have not been studied systematically. Thus, the aim of this study was to examine the neuropsychological profile of PD patients that carry the R1441G mutation in the LRRK2 gene and compare this to that of sporadic PD patients. Based on a previous study [5] that suggested that dementia might occur less frequently among patients with PD and LRRK2-R1441G mutation, we hypothesized that this group of patients would have milder cognitive deficits.
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2. Methods 2.1. Participants Patients with PD able to complete the neuropsychological assessment were selected from the database at our movement disorders clinic. First, R1441G-PD patients were invited to take part, with 30 patients completing the neuropsychological protocol. In the next step, 30 i-PD patients who did not carry the R1441G or G2019S mutations in LRRK2 gene were selected, and they were matched by demographic and clinical characteristics: age, gender, years of education, age at disease onset and years of disease duration. This study was approved by the Ethics Committee of the University Hospital Donostia and written informed consent was obtained from the participants. 2.2. Clinical and neuropsychological evaluation The clinical evaluation included a neurological examination and an evaluation of the patient's motor stage using the Hoehn and Yahr scale (H&Y) and the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS-III). A comprehensive neuropsychological battery was administered to all of the patients in the “ON” state by an experienced neuropsychologist blind to the mutation status. Five cognitive domains were assessed and two tasks/measures were selected for each domain to define the patient's cognitive status: Attention was assessed with TMT-A and LetterNumber (WAIS-III); Phonological Fluency-FAS and Stroop Color-Word interference task were selected to test Executive Function; Language was evaluated with the abbreviated Boston Naming Test and Semantic Fluency test (animals); Memory was tested with Rey's Auditive-Verbal Learning Test (RAVLT) total learning score and the RAVLT delayed recall score; and Visuoperceptive/visuospatial function was evaluated with the Object Decision and Number Location subtests from the VOSP battery. In addition, other measures were collected (TMT B, Stroop Words and Stroop Color) and the MMSE was administered to assess global cognition. The Interview for Deterioration in Daily Living in Dementia (IDDD) was used to assess functional impairment (cut-off score ¼ 39). Beck's Depression Inventory (BDI) was used to detect depressive syndrome (cut-off score ¼ 14) and the anxiety score of the Hospital Anxiety and Depression Scale (HADS-A) was use to assay symptoms of anxiety (cut-off score ¼ 11). Dementia was diagnosed according to the MDS criteria [6] and a diagnosis of PDMCI was made in non-demented patients following the level II category guidelines of the MDS [7]. Regarding PD-MCI, a cognitive complaint reported by either the patient or informant, or observed by the clinician was required for the diagnosis of PD-MCI, but cognitive deficits should not interfere significantly with daily living activities. Impairment in the neuropsychological tests was defined as performance at least 1.5 SD below normative data according to age and years of education. Single domain-MCI was diagnosed if the two tasks for a single cognitive domain were impaired. Multidomain-MCI was diagnosed when abnormalities were present in at least one task in two or more cognitive domains. For the diagnosis of PD-Dementia, an insidious onset of the cognitive decline from premorbid level, slow progression, impairment in at least two cognitive domains with deficits severe enough to impair activities of daily living (IDDD score >39) were required [6]. Patients who did not fulfil criteria for PD-MCI or PD-Dementia were considered to be cognitively normal.
than in the i-PD group (45%, n ¼ 9/20) but the difference was not statistically significant (Fisher's exact test p ¼ 0.093). The number of patients with anxiolytic medication was similar in the two groups (R1441G-PD: 27.3%, n ¼ 6/22 and i-PD: 35%, n ¼ 7/20; Fisher's exact test p ¼ 0.741). The neuropsychological test scores did not differ between the R1441G-PD and i-PD groups, although the R1441G-PD patients appeared to perform worse in the abbreviated Boston Naming test (p ¼ 0.03: Table 1), yet this difference was not significant when Bonferroni's correction for multiple comparisons was applied (p < 0.005). Among the R1441G-PD subjects, 56.7% (n ¼ 17) were classified as cognitively normal, 30% (n ¼ 9) as having PD-MCI and 13.3% (n ¼ 4) as having dementia. By contrast, 43.3% (n ¼ 13) of the i-PD patients were considered to be cognitively normal, 30% (n ¼ 9) were diagnosed as PD-MCI and 26.7% (n ¼ 8) met established criteria for dementia. To determine if the discrepancy in the distribution of PDDementia was statistically significant between the two groups, McNemar paired analysis for matched samples was performed, dividing the variable of cognitive status into PD-No Dementia (Normal Cognition and PD-MCI patients) and PD-Dementia. The proportion of discordant pairs in which PD-Dementia was present in the patients with i-PD but not in the R1441G-PD patients was 23.3%, while in 10% of the pairs PD-Dementia was recorded in R1441G-PD patients but not in the patients with i-PD. However, this difference was not statistically significant (McNemar-Bowker, p ¼ 0.344: Supplementary table). The type of domains impaired did not differ between R1441GPD and i-PD patients with PD-MCI and PD-Dementia (Fig. 1). In both PD-MCI groups the most frequently affected domains were memory, executive function and attention, whereas more generalized impairment was observed in the patients in the PDDementia group. Among R1441G-PD patients with MCI, 2 patients were diagnosed as single domain-MCI (20%) and 7 patients (80%) had multidomain-MCI. Likewise, one i-PD patient was classified as single domain-MCI (11.1%) and 8 such patients were considered as multidomain-MCI (88.9%). The number of impaired domains was also similar in the groups with PD-Dementia, with both i-PD and R1441G-PD patients having a median of 4 impaired domains (IQ range 3e4 or 4e4, respectively: ManneWhitney U ¼ 412.50; p ¼ 0.57).
2.3. Statistical analysis The data were analysed using SPSS software (version 21.00). The normality of the distribution was assessed using the KolmogoroveSmirnov test. Qualitative data were examined by Fisher's exact test or chi2 test and continuous variables were analysed using the Student-t or U-ManneWhitney test as appropriate. Bonferroni's correction for multiple comparisons was applied and a value of p < 0.005 was considered significant. The McNemar test was applied to evaluate differences in cognitive status between the R1441G-PD and i-PD groups (cognitively normal, PDMCI and PD-Dementia).
3. Results The two groups of patients had similar demographic and clinical features (Table 1) since they were matched previously. R1441G-PD patients consumed a slightly lower equivalent daily dose of L-dopa than i-PD patients, although this difference was not statistically significant. There were no significant differences in the mean scores and the prevalence of depression and anxiety between the two groups (Table 1). Depressive syndrome was detected in 31.8% (n ¼ 7/22) of R1441G-PD and 25% (n ¼ 5/20) of i-PD patients (Fisher's exact test p ¼ 0.738) and anxiety symptoms were observed in 4.5% (n ¼ 1/22) of R144G-PD and 15% (n ¼ 3/20) of i-PD (Fisher's exact test p ¼ 0.333). The frequency of patients on antidepressant therapy was somewhat smaller in the R1441G-PD group (18.2%, n ¼ 4/22)
4. Discussion This is the first study to analyse neuropsychological features in R1441G-PD and to compare these with a matched i-PD group of patients. Previous studies based on clinical observations in PD patients carrying R1441G [5] and G2019S mutations [8] suggested that dementia might occur less frequently in LRRK2-PD than in iPD. More recent studies in G2019S-PD patients assessed different cognitive domains [9e11] and when considering low and highly educated patients separately [10], similar cognitive abnormalities were found in G2019S-PD and i-PD patients, with executive function being most frequently impaired [9e10]. Likewise, in our detailed cognitive study using a wide neuropsychological battery to assess the different cognitive domains, we found that neuropsychological performance of R1441G-PD patients is similar to that of i-PD patients. In keeping with the literature, one third of the R1441G-PD and iPD patients studied were diagnosed as MCI [12]. It was surprising that the majority of MCI were diagnosed as multidomain-PD (80% of R1441G-PD and 88.9% of i-PD), although this is consistent with a recent study that found 93% multidomain-MCI in PD patients using the MDS Task Force criteria [13]. The profile of impaired domains we identified was also similar in the two groups, with memory,
A. Estanga et al. / Parkinsonism and Related Disorders 20 (2014) 1097e1100
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Table 1 Clinical and neuropsychological characteristics of R1441G-PD and i-PD patients.
Age Gender (m/f) Education (years)a Age at PD onset (years) Disease duration (years) Dominant onset symptom n (%) Tremor AR PIGD Levodopa equivalent dose Hoehn and Yahr stage UPDRS-III “On” Beck depression inventorya HADS-anxietya IDDD MMSEa Attention Trail making test Aa Number-letter (WAIS-III)a Executive function Stroop CW interference task Phonological fluency (FAS) Memory RAVLT total learning RAVLT delayed recall Language Category fluency (Animals) Boston naming (15 items) Visuoperceptive/visuospatial Object decision (VOSP) Number location (VOSP)a Other measures of attention and executive function Stroop word reading Stroop color naming Trail making test Ba
R1441G-PD n ¼ 30 mean ± SD (minemax)
i-PD n ¼ 30 mean ± SD (minemax)
p
69.97 ± 10.64 (44e86) 14/16 8 (6.75e10) 59.87 ± 9.56 (39e78) 10.13 ± 5.71 (1e23)
70.10 ± 10.02 (42e84) 13/17 8 (6.75e11.25) 60.33 ± 9.36 (40e80) 9.83 ± 5.86 (1e26)
0.960 1.000 0.869 0.849 0.842 0.837
15 (50%) 12 (40%) 3 (10%) 666.60 ± 335.91 (50e1200) 2.33 ± 0.87 (1e4) 18.86 ± 10.61 (n ¼ 29) 6 (2e12.25) (n ¼ 22) 3 (1e5) (n ¼ 22) 35.97 ± 6.64(33e63) 26 (24e27)
16 (53.3%) 10 (33.3%) 4 (13.3%) 835.87 ± 410.60 (50e1600) 2.48 ± 0.74(1e4) 21.17 ± 12.56 (n ¼ 28) 7.5 (5e10.75) (n ¼ 20) 3 (1.25e5) (n ¼ 20) 38.35 ± 6.88(33e63) 25 (23e28)
0.117 0.489 0.450 0.640 0.919 0.198 0.584
64 (43e111) 4.5 (3e6.75)
78 (46e127) 4 (2e8.5)
0.422 0.714
26.17 ± 11.18 (4e41) 23.36 ± 15.65 (0e62)
21.76 ± 11.33 (5e47) 22.86 ± 15.31 (1e54)
0.138 0.913
28.03 ± 11.12 (3e53) 4.97 ± 3.76 (0e13)
30.53 ± 11.41(10e58) 4.47 ± 3.61 (0e15)
0.394 0.601
15 ± 6.23 (4e32) 7.66 ± 2.38 (4e13)
16.47 ± 7.09 (5e36) 9.27 ± 3.20 (3e15)
0.398 0.033
14.27 ± 2.75 (8e20) 9 (6e10)
14.21 ± 3.20 (6e19) 8 (7e10)
0.947 0.204
81.28 ± 22.63 (26e122) 53.83 ± 15.36 (14e77) 300 (135e324)
78.82 ± 22.51 (33e132) 50.21 ± 16.18 (20e80) 287 (122.50e500)
0.683 0.391 0.281
Abbreviations: PD-R1441G, Parkinson's disease carriers of the R1441G mutation; i-PD, idiopathic Parkinson's disease; AR, Akinetic-Rigidity; PIGD, Postural instability and gait disability; UPDRS-III, Unified Parkinson's Disease Rating Scale motor score; IDDD, Interview for Deterioration in Daily Living in Dementia; MMSE, Mini Mental State Examination; WAIS-III, Wechsler Adult Intelligence Scale third edition; Stroop CW interference task, Stroop Color-Word interference task; RAVLT, Rey's Auditory Verbal Learning Test; VOSP, Visual Object and Space Perception Battery. a Corresponds to the results of the ManneWhitney test and data are given as median (interquartile range).
executive function, and attention most frequently altered. This is in line with the predominant frontostriatal attentional-executive pattern and memory impairments observed in MCI-PD patients [14]. It is important to note that while 8 patients (26.6%) in the i-PD group had dementia, only 4 patients (13.3%) of the R1441G-PD group were attributed this cognitive status, representing a 50% higher prevalence of dementia in the i-PD group of patients. Although this difference is not statistically significant, the small number of subjects prevents us from ruling out an underlying and clinically relevant difference. In fact, some of the initial studies suggested that alterations in executive function and attention are frequent in LRRK2-PD patients, while dementia is not so common [15]. It is difficult to estimate the prevalence of affective disorders due to the overlap between mood, motor and cognitive symptoms. Indeed, there are no data regarding this issue from R1441G-PD patients and the data available from G2019S-PD patients are discordant. Although some studies indicate that depression is more common in PD associated to the G2019S mutation in LRRK2 than in i-PD, with an estimated prevalence of 69% and 65%, respectively [9,10], no such differences were found elsewhere [11]. Similarly, the prevalence of anxiety in PD related to G2019S-LRRK2 differs across studies [10,11]. A meta-analysis showed that the prevalence of depression in PD varied from 13% to 89% with a weighted mean of 42% in studies using a cut-off on a depression rating scale [16]. The
presence of symptoms of anxiety may also vary depending upon the characteristics of the sample, although a study of a representative sample of 1449 PD patients indicates that such symptoms occur in nearly 20% of patients [17]. Here we found no differences in the prevalence of depressive symptoms and anxiety symptoms between R1441G-PD and i-PD. Although the prevalence of depression seems to be lower in the group of i-PD patients, it has to be considered that there were more patients with antidepressant treatment in this group and this fact might have influenced the result. The main strength of this study is that for the first time we have studied in depth the features of cognition, depression and anxiety in R1441G-PD patients, and compared them with a matched cohort of i-PD patients. This was achieved using a comprehensive battery of neuropsychological tests, considering the diagnosis of MCI and defining dementia as outlined by the MDS criteria. The main limitation is that although due to the ethnic background of carriers of this mutation this is a relatively large sample of PD patients carrying the R1441G mutation, the number is relatively small in terms of statistical power. In summary, in our study statistically significant differences were not detected between PD patients carrying the R1441G mutation and i-PD, concerning the prevalence and severity of depressive and anxious symptoms, or cognitive status, measured through individual test performance, number and type of cognitive domains impaired and prevalence of PD-MCI and PD-Dementia.
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Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2014.07.005. References
Fig. 1. Percentage of PD patients with MCI (A) and with dementia (B) who showed deficits in each one the different cognitive domains. All p values were calculated using the Fisher's exact test. (*) No statistics are computed because this variable is a constant. PD-MCI, Parkinson's disease associated mild cognitive impairment; PD-Dementia, Parkinson's disease associated dementia; ATT, Attention; EF, Executive Function; VSP, Visuospatial; LNG, Language; MEM, Memory.
Conflict of interest No conflict of interests to declare. Acknowledgements The authors are grateful to the patients for participating in this study and they wish to thank Cristina Sarasqueta for assistance with the statistical analysis and Connie Marras for her careful reading of the manuscript. A.E. received a PhD fellowship from the Ilundain Fundazioa-Foundation for the neurological studies.
[1] Gorostidi A, Ruiz-Martinez J, Lopez de MA, Alzualde A, Marti Masso JF. LRRK2 G2019S and R1441G mutations associated with Parkinson's disease are common in the Basque Country, but relative prevalence is determined by ethnicity. Neurogenetics 2009 Apr;10(2):157e9. [2] Mata IF, Ross OA, Kachergus J, Huerta C, Ribacoba R, Moris G, et al. LRRK2 mutations are a common cause of Parkinson’s disease in Spain. Eur J Neurol 2006;13:391e4. mez-Esteban JC, Gomez[3] Gonzalez-Fernandez MC, Lezcano E, Ross OA, Go Busto F, Velasco F. LRRK2-associated parkinsonism is a major cause of disease in Northern Spain. Parkinsonism Relat Disord 2007;13:509e15. ~ oz E, Vallderiola F, Tolosa E. LRRK2 muta[4] Gaig C, Ezquerra M, Martí MJ, Mun tions in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance. Arch Neurol 2006;63:377e82. [5] Paisan-Ruiz C, Saenz A, Lopez de MA, Marti I, Martinez GA, Marti-Masso JF, et al. Familial Parkinson's disease: clinical and genetic analysis of four Basque families. Ann Neurol 2005 Mar;57(3):365e72. [6] Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord 2007 Sep 15;22(12):1689e707. [7] Litvan I, Goldman JG, Troster AI, Schmand BA, Weintraub D, Petersen RC, et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: movement Disorder Society Task Force guidelines. Mov Disord 2012 Mar;27(3):349e56. [8] Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 2008 Jul;7(7): 583e90. [9] Goldwurm S, Zini M, Di FA, De GD, Siri C, Simons EJ, et al. LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006 Oct;12(7):410e9. [10] Belarbi S, Hecham N, Lesage S, Kediha MI, Smail N, Benhassine T, et al. LRRK2 G2019S mutation in Parkinson's disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism Relat Disord 2010 Dec;16(10):676e9. [11] Shanker V, Groves M, Heiman G, Palmese C, Saunders-Pullman R, Ozelius L, et al. Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. Mov Disord 2011 Aug 15;26(10):1875e80. [12] Litvan I, Aarsland D, Adler CH, Goldman JG, Kulisevsky J, Mollenhauer B, et al. MDS task force on mild cognitive impairment in Parkinson's disease: critical review of PD-MCI. Mov Disord 2011 Aug 15;26(10):1814e24. [13] Marras C, Armstrong MJ, Meaney CA, Fox S, Rothberg B, Reginold W, et al. Measuring mild cognitive impairment in patients with Parkinson's disease. Mov Disord 2013 May;28(5):626e33. http://dx.doi.org/10.1002/mds.25426. [14] Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 2010 Sep 21;75(12):1062e9. [15] Berg D, Schweitzer KJ, Leitner P, Zimprich A, Lichtner P, Belcredi P, et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*. Brain 2005 Dec;128(Pt 12):3000e11. [16] Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF. A systematic review of prevalence studies of depression in Parkinson's disease. Mov Disord 2008 Jan 30;23(2):183e9. [17] Riedel O, Klotsche J, Spottke A, Deuschl G, Forstl H, Henn F, et al. Frequency of dementia, depression, and other neuropsychiatric symptoms in 1,449 outpatients with Parkinson's disease. J Neurol 2010 Jul;257(7):1073e82.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Short communication
Cognitive dysfunction in Parkinson's disease related to the R1441G mutation in LRRK2 A. Estanga a, d, *, M.C. Rodriguez-Oroz a, b, c, J. Ruiz-Martinez a, b, M. Barandiaran a, b, A. Gorostidi a, A. Bergareche a, b, E. Mondragon a, b, A. Lopez de Munain a, b, d, J.F. Marti-Masso a, b, d a
Neuroscience Unit, Biodonostia Research Institute, San Sebastian, Spain Department of Neurology, University Hospital Donostia, San Sebastian, Spain Ikerbasque, Basque Foundation for Science, Bilbao, Spain d Department of Neuroscience, University of the Basque Country UPV/EHU, Spain b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 3 December 2013 Received in revised form 23 June 2014 Accepted 9 July 2014
Objective: The neuropsychological characteristics of patients with Parkinson's Disease (PD) associated with R1441G mutation in the LRRK2 gene (R1441G-PD) are not well known. The aim of this study was to examine the cognitive status and mood of R1441G-PD patients. Methods: Thirty patients with R1441G-PD were compared with thirty idiopathic PD (i-PD) patients who were matched by age, sex, education, disease onset age and duration, using a comprehensive battery of neuropsychological test, and considering the Movement Disorder Society (MDS) criteria for the diagnosis of Mild Cognitive Impairment (PD-MCI) and dementia (PD-Dementia). Results: The mean scores in the depression and anxiety scales were similar in the two groups. Depressive symptoms were detected in 31.8% of R1441G-PD and 25% of i-PD patients and anxiety symptoms were evident in 4.5% and 15%, respectively, but the differences were not significant. The only neuropsychological test on which there was a significantly worse performance in the R1441G-PD group was the Boston naming test but the difference became not significant when Bonferroni's correction was applied. The prevalence of PD-MCI was 30% in both R1441G-PD and i-PD, with no differences in the number and type of domains altered given that executive function, memory and attention were mainly affected. PDDementia was diagnosed in 13.3% (n ¼ 4) of R1441G-PD and 26.7% (n ¼ 8) of i-PD patients (difference was not significant). Conclusion: In conclusion, significant differences were not detected between R1441G-PD and i-PD in cognitive, depression and anxiety scales, or PD-MCI and PD-Dementia prevalence, and the cognitive profile was identical in the two groups. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Cognitive impairment Mood Parkinson's disease R1441G mutation LRRK2
1. Background LRRK2 mutations are the most common known genetic cause of autosomal dominant PD. The LRRK2-R1441G mutation has been found to be responsible of 46% of familial PD and 2.5% of sporadic PD in patients of basque origin in Gipuzkoa (Spain) [1]. The R1441G mutation is also identified at lower frequencies in patients from
* Corresponding author. Neurology Department, University Hospital Donostia, Paseo Dr. Beguiristain 107-116, 20014, San Sebastian, Spain. Tel.: þ34 943007145. E-mail addresses: [email protected], ainaraestanga@gmail. com (A. Estanga). http://dx.doi.org/10.1016/j.parkreldis.2014.07.005 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
nearby provinces (2.2% in Asturias [2], 1% in Cantabria [3], 0.7% in Catalonia [4]) but it is very rare outside Northern Spain. The clinical features of PD patients with this mutation are similar to those with sporadic PD, although a more “benign” progression of the disease evolving less often into dementia has been reported [2]. Nevertheless, the neuropsychological features of these patients have not been studied systematically. Thus, the aim of this study was to examine the neuropsychological profile of PD patients that carry the R1441G mutation in the LRRK2 gene and compare this to that of sporadic PD patients. Based on a previous study [5] that suggested that dementia might occur less frequently among patients with PD and LRRK2-R1441G mutation, we hypothesized that this group of patients would have milder cognitive deficits.
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2. Methods 2.1. Participants Patients with PD able to complete the neuropsychological assessment were selected from the database at our movement disorders clinic. First, R1441G-PD patients were invited to take part, with 30 patients completing the neuropsychological protocol. In the next step, 30 i-PD patients who did not carry the R1441G or G2019S mutations in LRRK2 gene were selected, and they were matched by demographic and clinical characteristics: age, gender, years of education, age at disease onset and years of disease duration. This study was approved by the Ethics Committee of the University Hospital Donostia and written informed consent was obtained from the participants. 2.2. Clinical and neuropsychological evaluation The clinical evaluation included a neurological examination and an evaluation of the patient's motor stage using the Hoehn and Yahr scale (H&Y) and the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS-III). A comprehensive neuropsychological battery was administered to all of the patients in the “ON” state by an experienced neuropsychologist blind to the mutation status. Five cognitive domains were assessed and two tasks/measures were selected for each domain to define the patient's cognitive status: Attention was assessed with TMT-A and LetterNumber (WAIS-III); Phonological Fluency-FAS and Stroop Color-Word interference task were selected to test Executive Function; Language was evaluated with the abbreviated Boston Naming Test and Semantic Fluency test (animals); Memory was tested with Rey's Auditive-Verbal Learning Test (RAVLT) total learning score and the RAVLT delayed recall score; and Visuoperceptive/visuospatial function was evaluated with the Object Decision and Number Location subtests from the VOSP battery. In addition, other measures were collected (TMT B, Stroop Words and Stroop Color) and the MMSE was administered to assess global cognition. The Interview for Deterioration in Daily Living in Dementia (IDDD) was used to assess functional impairment (cut-off score ¼ 39). Beck's Depression Inventory (BDI) was used to detect depressive syndrome (cut-off score ¼ 14) and the anxiety score of the Hospital Anxiety and Depression Scale (HADS-A) was use to assay symptoms of anxiety (cut-off score ¼ 11). Dementia was diagnosed according to the MDS criteria [6] and a diagnosis of PDMCI was made in non-demented patients following the level II category guidelines of the MDS [7]. Regarding PD-MCI, a cognitive complaint reported by either the patient or informant, or observed by the clinician was required for the diagnosis of PD-MCI, but cognitive deficits should not interfere significantly with daily living activities. Impairment in the neuropsychological tests was defined as performance at least 1.5 SD below normative data according to age and years of education. Single domain-MCI was diagnosed if the two tasks for a single cognitive domain were impaired. Multidomain-MCI was diagnosed when abnormalities were present in at least one task in two or more cognitive domains. For the diagnosis of PD-Dementia, an insidious onset of the cognitive decline from premorbid level, slow progression, impairment in at least two cognitive domains with deficits severe enough to impair activities of daily living (IDDD score >39) were required [6]. Patients who did not fulfil criteria for PD-MCI or PD-Dementia were considered to be cognitively normal.
than in the i-PD group (45%, n ¼ 9/20) but the difference was not statistically significant (Fisher's exact test p ¼ 0.093). The number of patients with anxiolytic medication was similar in the two groups (R1441G-PD: 27.3%, n ¼ 6/22 and i-PD: 35%, n ¼ 7/20; Fisher's exact test p ¼ 0.741). The neuropsychological test scores did not differ between the R1441G-PD and i-PD groups, although the R1441G-PD patients appeared to perform worse in the abbreviated Boston Naming test (p ¼ 0.03: Table 1), yet this difference was not significant when Bonferroni's correction for multiple comparisons was applied (p < 0.005). Among the R1441G-PD subjects, 56.7% (n ¼ 17) were classified as cognitively normal, 30% (n ¼ 9) as having PD-MCI and 13.3% (n ¼ 4) as having dementia. By contrast, 43.3% (n ¼ 13) of the i-PD patients were considered to be cognitively normal, 30% (n ¼ 9) were diagnosed as PD-MCI and 26.7% (n ¼ 8) met established criteria for dementia. To determine if the discrepancy in the distribution of PDDementia was statistically significant between the two groups, McNemar paired analysis for matched samples was performed, dividing the variable of cognitive status into PD-No Dementia (Normal Cognition and PD-MCI patients) and PD-Dementia. The proportion of discordant pairs in which PD-Dementia was present in the patients with i-PD but not in the R1441G-PD patients was 23.3%, while in 10% of the pairs PD-Dementia was recorded in R1441G-PD patients but not in the patients with i-PD. However, this difference was not statistically significant (McNemar-Bowker, p ¼ 0.344: Supplementary table). The type of domains impaired did not differ between R1441GPD and i-PD patients with PD-MCI and PD-Dementia (Fig. 1). In both PD-MCI groups the most frequently affected domains were memory, executive function and attention, whereas more generalized impairment was observed in the patients in the PDDementia group. Among R1441G-PD patients with MCI, 2 patients were diagnosed as single domain-MCI (20%) and 7 patients (80%) had multidomain-MCI. Likewise, one i-PD patient was classified as single domain-MCI (11.1%) and 8 such patients were considered as multidomain-MCI (88.9%). The number of impaired domains was also similar in the groups with PD-Dementia, with both i-PD and R1441G-PD patients having a median of 4 impaired domains (IQ range 3e4 or 4e4, respectively: ManneWhitney U ¼ 412.50; p ¼ 0.57).
2.3. Statistical analysis The data were analysed using SPSS software (version 21.00). The normality of the distribution was assessed using the KolmogoroveSmirnov test. Qualitative data were examined by Fisher's exact test or chi2 test and continuous variables were analysed using the Student-t or U-ManneWhitney test as appropriate. Bonferroni's correction for multiple comparisons was applied and a value of p < 0.005 was considered significant. The McNemar test was applied to evaluate differences in cognitive status between the R1441G-PD and i-PD groups (cognitively normal, PDMCI and PD-Dementia).
3. Results The two groups of patients had similar demographic and clinical features (Table 1) since they were matched previously. R1441G-PD patients consumed a slightly lower equivalent daily dose of L-dopa than i-PD patients, although this difference was not statistically significant. There were no significant differences in the mean scores and the prevalence of depression and anxiety between the two groups (Table 1). Depressive syndrome was detected in 31.8% (n ¼ 7/22) of R1441G-PD and 25% (n ¼ 5/20) of i-PD patients (Fisher's exact test p ¼ 0.738) and anxiety symptoms were observed in 4.5% (n ¼ 1/22) of R144G-PD and 15% (n ¼ 3/20) of i-PD (Fisher's exact test p ¼ 0.333). The frequency of patients on antidepressant therapy was somewhat smaller in the R1441G-PD group (18.2%, n ¼ 4/22)
4. Discussion This is the first study to analyse neuropsychological features in R1441G-PD and to compare these with a matched i-PD group of patients. Previous studies based on clinical observations in PD patients carrying R1441G [5] and G2019S mutations [8] suggested that dementia might occur less frequently in LRRK2-PD than in iPD. More recent studies in G2019S-PD patients assessed different cognitive domains [9e11] and when considering low and highly educated patients separately [10], similar cognitive abnormalities were found in G2019S-PD and i-PD patients, with executive function being most frequently impaired [9e10]. Likewise, in our detailed cognitive study using a wide neuropsychological battery to assess the different cognitive domains, we found that neuropsychological performance of R1441G-PD patients is similar to that of i-PD patients. In keeping with the literature, one third of the R1441G-PD and iPD patients studied were diagnosed as MCI [12]. It was surprising that the majority of MCI were diagnosed as multidomain-PD (80% of R1441G-PD and 88.9% of i-PD), although this is consistent with a recent study that found 93% multidomain-MCI in PD patients using the MDS Task Force criteria [13]. The profile of impaired domains we identified was also similar in the two groups, with memory,
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Table 1 Clinical and neuropsychological characteristics of R1441G-PD and i-PD patients.
Age Gender (m/f) Education (years)a Age at PD onset (years) Disease duration (years) Dominant onset symptom n (%) Tremor AR PIGD Levodopa equivalent dose Hoehn and Yahr stage UPDRS-III “On” Beck depression inventorya HADS-anxietya IDDD MMSEa Attention Trail making test Aa Number-letter (WAIS-III)a Executive function Stroop CW interference task Phonological fluency (FAS) Memory RAVLT total learning RAVLT delayed recall Language Category fluency (Animals) Boston naming (15 items) Visuoperceptive/visuospatial Object decision (VOSP) Number location (VOSP)a Other measures of attention and executive function Stroop word reading Stroop color naming Trail making test Ba
R1441G-PD n ¼ 30 mean ± SD (minemax)
i-PD n ¼ 30 mean ± SD (minemax)
p
69.97 ± 10.64 (44e86) 14/16 8 (6.75e10) 59.87 ± 9.56 (39e78) 10.13 ± 5.71 (1e23)
70.10 ± 10.02 (42e84) 13/17 8 (6.75e11.25) 60.33 ± 9.36 (40e80) 9.83 ± 5.86 (1e26)
0.960 1.000 0.869 0.849 0.842 0.837
15 (50%) 12 (40%) 3 (10%) 666.60 ± 335.91 (50e1200) 2.33 ± 0.87 (1e4) 18.86 ± 10.61 (n ¼ 29) 6 (2e12.25) (n ¼ 22) 3 (1e5) (n ¼ 22) 35.97 ± 6.64(33e63) 26 (24e27)
16 (53.3%) 10 (33.3%) 4 (13.3%) 835.87 ± 410.60 (50e1600) 2.48 ± 0.74(1e4) 21.17 ± 12.56 (n ¼ 28) 7.5 (5e10.75) (n ¼ 20) 3 (1.25e5) (n ¼ 20) 38.35 ± 6.88(33e63) 25 (23e28)
0.117 0.489 0.450 0.640 0.919 0.198 0.584
64 (43e111) 4.5 (3e6.75)
78 (46e127) 4 (2e8.5)
0.422 0.714
26.17 ± 11.18 (4e41) 23.36 ± 15.65 (0e62)
21.76 ± 11.33 (5e47) 22.86 ± 15.31 (1e54)
0.138 0.913
28.03 ± 11.12 (3e53) 4.97 ± 3.76 (0e13)
30.53 ± 11.41(10e58) 4.47 ± 3.61 (0e15)
0.394 0.601
15 ± 6.23 (4e32) 7.66 ± 2.38 (4e13)
16.47 ± 7.09 (5e36) 9.27 ± 3.20 (3e15)
0.398 0.033
14.27 ± 2.75 (8e20) 9 (6e10)
14.21 ± 3.20 (6e19) 8 (7e10)
0.947 0.204
81.28 ± 22.63 (26e122) 53.83 ± 15.36 (14e77) 300 (135e324)
78.82 ± 22.51 (33e132) 50.21 ± 16.18 (20e80) 287 (122.50e500)
0.683 0.391 0.281
Abbreviations: PD-R1441G, Parkinson's disease carriers of the R1441G mutation; i-PD, idiopathic Parkinson's disease; AR, Akinetic-Rigidity; PIGD, Postural instability and gait disability; UPDRS-III, Unified Parkinson's Disease Rating Scale motor score; IDDD, Interview for Deterioration in Daily Living in Dementia; MMSE, Mini Mental State Examination; WAIS-III, Wechsler Adult Intelligence Scale third edition; Stroop CW interference task, Stroop Color-Word interference task; RAVLT, Rey's Auditory Verbal Learning Test; VOSP, Visual Object and Space Perception Battery. a Corresponds to the results of the ManneWhitney test and data are given as median (interquartile range).
executive function, and attention most frequently altered. This is in line with the predominant frontostriatal attentional-executive pattern and memory impairments observed in MCI-PD patients [14]. It is important to note that while 8 patients (26.6%) in the i-PD group had dementia, only 4 patients (13.3%) of the R1441G-PD group were attributed this cognitive status, representing a 50% higher prevalence of dementia in the i-PD group of patients. Although this difference is not statistically significant, the small number of subjects prevents us from ruling out an underlying and clinically relevant difference. In fact, some of the initial studies suggested that alterations in executive function and attention are frequent in LRRK2-PD patients, while dementia is not so common [15]. It is difficult to estimate the prevalence of affective disorders due to the overlap between mood, motor and cognitive symptoms. Indeed, there are no data regarding this issue from R1441G-PD patients and the data available from G2019S-PD patients are discordant. Although some studies indicate that depression is more common in PD associated to the G2019S mutation in LRRK2 than in i-PD, with an estimated prevalence of 69% and 65%, respectively [9,10], no such differences were found elsewhere [11]. Similarly, the prevalence of anxiety in PD related to G2019S-LRRK2 differs across studies [10,11]. A meta-analysis showed that the prevalence of depression in PD varied from 13% to 89% with a weighted mean of 42% in studies using a cut-off on a depression rating scale [16]. The
presence of symptoms of anxiety may also vary depending upon the characteristics of the sample, although a study of a representative sample of 1449 PD patients indicates that such symptoms occur in nearly 20% of patients [17]. Here we found no differences in the prevalence of depressive symptoms and anxiety symptoms between R1441G-PD and i-PD. Although the prevalence of depression seems to be lower in the group of i-PD patients, it has to be considered that there were more patients with antidepressant treatment in this group and this fact might have influenced the result. The main strength of this study is that for the first time we have studied in depth the features of cognition, depression and anxiety in R1441G-PD patients, and compared them with a matched cohort of i-PD patients. This was achieved using a comprehensive battery of neuropsychological tests, considering the diagnosis of MCI and defining dementia as outlined by the MDS criteria. The main limitation is that although due to the ethnic background of carriers of this mutation this is a relatively large sample of PD patients carrying the R1441G mutation, the number is relatively small in terms of statistical power. In summary, in our study statistically significant differences were not detected between PD patients carrying the R1441G mutation and i-PD, concerning the prevalence and severity of depressive and anxious symptoms, or cognitive status, measured through individual test performance, number and type of cognitive domains impaired and prevalence of PD-MCI and PD-Dementia.
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Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2014.07.005. References
Fig. 1. Percentage of PD patients with MCI (A) and with dementia (B) who showed deficits in each one the different cognitive domains. All p values were calculated using the Fisher's exact test. (*) No statistics are computed because this variable is a constant. PD-MCI, Parkinson's disease associated mild cognitive impairment; PD-Dementia, Parkinson's disease associated dementia; ATT, Attention; EF, Executive Function; VSP, Visuospatial; LNG, Language; MEM, Memory.
Conflict of interest No conflict of interests to declare. Acknowledgements The authors are grateful to the patients for participating in this study and they wish to thank Cristina Sarasqueta for assistance with the statistical analysis and Connie Marras for her careful reading of the manuscript. A.E. received a PhD fellowship from the Ilundain Fundazioa-Foundation for the neurological studies.
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